Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by pathogenic variants in sarcomeric genes, leading to left ventricular hypertrophy and complex phenotypic heterogeneity. While HCM is the most common inherited cardiomyopathy, pharmacological treatment options have previously been limited and were predominantly directed towards symptom control owing to left ventricular outflow obstruction. These therapies, including beta blockers, calcium channel blockers, and disopyramide, have not been shown to affect the natural history of the disease, which is of particular concern for younger patients who have an increased lifetime risk of experiencing arrhythmias, heart failure, and sudden cardiac death. Increased knowledge of the genetic mechanisms underlying this disease in recent years has led to the development of targeted, potentially disease-modifying therapies for both obstructive and nonobstructive phenotypes that may help to prevent or ameliorate left ventricular hypertrophy. In this review article, we will define the etiology and clinical phenotypes of HCM, summarize the conventional therapies for obstructive HCM, discuss the emerging targeted therapies as well as novel invasive approaches for obstructive HCM, describe the therapeutic advances for nonobstructive HCM, and outline the future directions for the treatment of HCM.

‘Genome-first’ approaches to analyzing rare variants can reveal new insights into human biology and disease. Because pathogenic variants are often rare, new discovery requires aggregating rare coding variants into ‘gene burdens’ for sufficient power. However, a major challenge is deciding which variants to include in gene burden tests. Pathogenic variants in MYBPC3 and MYH7 are well-known causes of hypertrophic cardiomyopathy (HCM), and focusing on these ‘positive control’ genes in a genome-first approach could help inform variant selection methods and gene burdening strategies for other genes and diseases. Integrating exome sequences with electronic health records among 41 759 participants in the Penn Medicine BioBank, we evaluated the performance of aggregating predicted loss-of-function (pLOF) and/or predicted deleterious missense (pDM) variants in MYBPC3 and MYH7 for gene burden phenome-wide association studies (PheWAS). The approach to grouping rare variants for these two genes produced very different results: pLOFs but not pDM variants in MYBPC3 were strongly associated with HCM, whereas the opposite was true for MYH7. Detailed review of clinical charts revealed that only 38.5% of patients with HCM diagnoses carrying an HCM-associated variant in MYBPC3 or MYH7 had a clinical genetic test result. Additionally, 26.7% of MYBPC3 pLOF carriers without HCM diagnoses had clear evidence of left atrial enlargement and/or septal/LV hypertrophy on echocardiography. Our study shows the importance of evaluating both pLOF and pDM variants for gene burden testing in future studies to uncover novel gene-disease relationships and identify new pathogenic loss-of-function variants across the human genome through genome-first analyses of healthcare-based populations.

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Postpartum cardiovascular (CV) evaluation of women with preeclampsia is recommended to screen for and treat modifiable risk factors to reduce lifetime CV risk. However, attendance at in-person postpartum obstetric and cardiology clinic visits is low. The aim of this study was to compare the completion rate of new patient telemedicine visits to in-person office visits for patients with preeclampsia referred for postpartum hypertension management and CV risk assessment at a single center. There were 236 unique new patient visits scheduled during the study period. The average age was 30.3 years, 73.7% patients were Black, and 56.7% had Medicaid insurance. The completion rate was 32% for in-person clinic visits and 70% for telemedicine visits. Women who did not complete an office visit were more likely to be Black (87% vs. 56%, p < 0.01) and younger (29.1 vs. 31.4 years, p = 0.04) compared to those who completed a visit. Notably, this difference was not seen with telemedicine visits. Telemedicine may provide a novel opportunity to improve the care for blood pressure management and CV risk reduction in a vulnerable population at risk of premature CV disease.

Introduction: The genetic architecture of peripartum cardiomyopathy (PPCM) and dilated cardiomyopathy (DCM) overlap, and 15% of patients with PPCM have a disease-causing variant in a DCM-associated gene. Despite the impact of genetics on cascade screening and risk stratification, there are no recommendations for genetic testing in PPCM. We aimed to quantify the percentage of individuals with PPCM referred for genetic testing and to identify factors that may impact the likelihood of referral for genetic testing. Methods : We conducted a retrospective cohort study of 205 patients diagnosed with PPCM from 1986-2018 within the University of Pennsylvania Health System who had outpatient follow-up. We determined the referral rate for genetic testing and examined differences in referral based on race, timing of PPCM diagnosis, hypertensive disorders of pregnancy (HDP), NYHA class at diagnosis, LVEF at diagnosis, family history, recurrent PPCM, and referral to a heart failure specialist. We compared continuous variables using the Student t test and categorical variables using Pearson’s chi-square test. Results : Of 205 patients with PPCM, 23 (11%) were referred for genetic testing. Women referred for genetic testing were more likely to have HDP (61% vs. 37%, p=0.03), LVEF <30% at diagnosis (65% vs. 42%, p=0.04), recurrent PPCM (17% vs. 5%, p=0.04), a first-degree family member with heart failure or cardiomyopathy (70% vs. 17%, p<0.001), and any documented family history at the first cardiology visit (78% vs. 54%, p=0.03). Of those referred, 17 (74%) underwent genetic counseling, and 12 (52%) completed genetic testing. Two patients (17%) had a pathogenic or likely pathogenic variant in TTN and were recommended for cascade screening, and 9 (75%) had variants of unknown significance which were predominately missense variants. Conclusions : A minority of women with PPCM are referred for genetic testing. Referral is largely driven by family history, which may lead to under-diagnosis of pathogenic mutations. Increasing referral rates may improve the detection of pathogenic mutations which may impact the care provided to affected women and their families.